Presence of koilocytes in actinic keratosis identifies those at high risk of developing keratinocyte carcinoma

BACKGROUND: Keratinocyte carcinoma (KC) rates continue to increase, despite current prevention strategies. Effective treatment of actinic keratoses (AKs) can reduce the risk of subsequent KC; however, the prevalence of AKs precludes treating all individuals. Recently, we identified a subset of human papillomavirus 8 (HPV8)-associated AKs. Hence, further stratification is needed to better identify patients at high risk of KC. OBJECTIVES: To determine the association of HPV8 with subsequent KC and identify specific treatment. METHODS: Patients with a prior history of pathologist-proven AK were recruited. Histology samples were analysed for HPV8, and medical records were reviewed for KC. HPV8-associated human AK, cell lines and mouse models were interrogated for expression of Src family kinases. The in vitro and in vivo biologic effects of Src inhibition were determined using small interfering RNA and tirbanibulin. RESULTS: Sixty-one patients with AK without a history of antecedent KC were divided into those with (n = 31) and without HPV8 (n = 30) infection. Using multivariable Cox regression with data adjusted for sex, age and body site, patients with HPV8-associated AKs had a greater risk of subsequent KC (hazard ratio 5.5, 95% confidence interval 2.3-12.9; P < 0.001). Independently, HPV8-associated AKs were associated with invasive squamous cell [odds ratio (OR) 32.0; P < 0.001] and basal cell carcinoma (OR 4.5; P < 0.01), and included all nine patients with multiple KCs. HPV8-associated AKs showed elevated expression of phosphorylated Src kinase. Inhibition of Src reduced cell proliferation and blocked colony-forming efficiency. In vivo, Src inhibition restored epidermal thickness and hindered the development of skin tumours. CONCLUSIONS: The presence of koilocytes in AK histology is indicative of a subset of patients at risk of multiple KCs. Inhibiting Src kinase blocked this HPV8-associated keratinocyte proliferation and prevented skin tumours in a mouse model.